DESCRIPTION: Smoking is an important public health problem costing over 430,000 lives a year in this county alone. The first line-treatments, Nicotine Replacement Treatments (NRT) or bupropion, compared to placebo, approximately double the long-term success rate for smoking cessation. Given that there remains 46 million smokers in this country and over 70 percent of them interested in quitting smoking, development of new treatments for smoking cessation will have great public health implications. The primary aim of this proposal is to determine the utility of the gamma-aminobutyric acid (GABA) system as a target for the treatment of tobacco dependence. This proposal is based on the findings of our pilot study, which examined the interactions between a selective GABA transporter inhibitor, tiagabine, and nicotine in overnight abstinent smokers.In our pilot study, tiagabine, compared to placebo, attenuated the ratings of "good effects" and "drug liking" from IV nicotine in overnight abstinent smokers. Tiagabine treatment also decreased craving for cigarettes and improved performance on a reaction time test in abstinent smokers. These findings suggest that enhancing the GABA system may attenuate the reinforcing effects of nicotine and craving for cigarettes. In addition, our findings raise an interesting possibility that enhancing the GABA system with tiagabine may improve cognitive performance in abstinent smokers. Thus, medications increasing synaptic GABA levels may have utility for the pharmacotherapy of tobacco dependence. In this proposal, we will examine dosedependent effects of a GABA enhancing medication, tiagabine, (0, 8 or 16 mg), on smoking behavior and reactivity to smoking cues using human laboratory models. We hypothesize that in abstinent male and female smokers, tiagabine at 16 mg, will be most effective in decreasing smoking behavior and attenuating reactivity to smoking cues. This proposal will use validated human laboratory models to systematically investigate the potential utility of a GABA enhancing agent, tiagabine, as a pharmacological treatment for smoking cessation. Our proposed study will also provide critical information relevant for further clinical studies: the optimum dose and possible mechanism of action of tiagabine for tobacco dependence. The findings of this study will provide valuable information to develop new pharmacotherapies for smoking cessation.